U.S. patent number 8,579,990 [Application Number 13/075,531] was granted by the patent office on 2013-11-12 for tissue repair devices of rapid therapeutic absorbency.
This patent grant is currently assigned to Ethicon, Inc.. The grantee listed for this patent is Joerg Priewe. Invention is credited to Joerg Priewe.
United States Patent |
8,579,990 |
Priewe |
November 12, 2013 |
Tissue repair devices of rapid therapeutic absorbency
Abstract
Novel implantable tissue repair medical devices are disclosed.
The devices have a central fabric member having anti-adhesion films
on both opposed sides. The films have pores, and are arranged such
that the pores on the opposed films are offset. The devices are
useful in hernia repair procedures.
Inventors: |
Priewe; Joerg (Krummbogen,
DE) |
Applicant: |
Name |
City |
State |
Country |
Type |
Priewe; Joerg |
Krummbogen |
N/A |
DE |
|
|
Assignee: |
Ethicon, Inc. (Somerville,
NJ)
|
Family
ID: |
45955127 |
Appl.
No.: |
13/075,531 |
Filed: |
March 30, 2011 |
Prior Publication Data
|
|
|
|
Document
Identifier |
Publication Date |
|
US 20120253472 A1 |
Oct 4, 2012 |
|
Current U.S.
Class: |
623/23.72 |
Current CPC
Class: |
A61L
31/146 (20130101); A61L 27/56 (20130101); A61P
31/00 (20180101); A61L 27/14 (20130101); A61L
31/04 (20130101); A61P 41/00 (20180101); A61L
31/16 (20130101) |
Current International
Class: |
A61F
2/02 (20060101) |
Field of
Search: |
;606/151
;623/1.13,1.39,1.46,23.72 ;600/37 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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1237588 |
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Dec 2004 |
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EP |
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1541183 |
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Jun 2005 |
|
EP |
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1558173 |
|
Aug 2005 |
|
EP |
|
1558173 |
|
Feb 2008 |
|
EP |
|
1541183 |
|
Aug 2009 |
|
EP |
|
01/85248 |
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Nov 2001 |
|
WO |
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WO 03041613 |
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May 2003 |
|
WO |
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WO 03099160 |
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Dec 2003 |
|
WO |
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WO 2010093333 |
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Aug 2010 |
|
WO |
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2010/124844 |
|
Nov 2010 |
|
WO |
|
Other References
Yoon Jeong Park et al.,"Porous poly(L-lactide) membranes for guided
tissue regeneration and controlled drug delivery: membrane
fabrication and characterization" Journal of Controlled Release 43
(1997) 151-160. cited by applicant.
|
Primary Examiner: Tyson; Melanie
Attorney, Agent or Firm: Skula; E. Richard
Claims
What is claimed is:
1. A tissue implant medical device, comprising: a tissue repair
member having a plurality of member pores, the repair member having
opposed first and second sides; a first polymer film, having first
film pores, the first polymer film mounted to the first side of the
member; and, a second polymer film, having second film pores, the
second polymer film mounted to the second side of the repair
member, wherein the first film pores are not in alignment with the
second film pores.
2. The medical device of claim 1, further comprising an active
agent.
3. The medical device of claim 2, wherein the active agent is
selected from the group consisting of, antibiotics,
chemotherapeutics, cytostatics, metastasis inhibitors,
antidiabetics, antimycotics, antimicrobials, antibacterials,
vitamins, gynaecological agents, urological agents, anti-allergic
agents, sexual hormones, sexual hormone inhibitors, local
anesthetics, haemostyptics, hormones, peptide hormones, vitamins,
antidepressants, anti-histamines, naked DNA, plasmid DNA, cationic
DNA complexes, RNA, cell constituents, vaccines, cells occurring
naturally in the body, genetically modified cells and combinations
thereof.
4. The medical device of claim 3, wherein the active agent is an
antimicrobial selected from the group consisting of octenidine,
PHMB, triclosan, copper, silver, nanosilver, gold, selenium,
gallium, taurolidine, cyclotaurolidine, N-chlorotaurine, alcohol,
LAE, MAPD, OAPD, and mixtures thereof.
5. The medical device of claim 4, wherein the antimicrobial is
triclosan.
6. The medical device of claim 4, wherein the antimicrobial is
octenidine.
7. The medical device of claim 4, wherein the antimicrobial is
PHMB.
8. The medical device of claim 1, wherein the tissue repair member
is a fabric.
9. The medical device of claim 8, wherein the tissue repair fabric
is selected from the group consisting of meshes, woven fabrics,
nonwoven fabrics and tapes.
10. The medical device of claim 9, wherein the tissue repair fabric
comprises a mesh.
11. The medical device of claim 1, wherein the tissue repair member
comprises a biocompatible nonabsorbable polymer selected from the
group consisting of polyalkenes, polypropylene, polyethylene,
fluorinated polyolefins, polytetrafluoroethylene,
polyvinylidenefluoride, polyamides, polyurethanes, polyisoprenes,
polystyrenes, polysilicones, polycarbonates, polyaryletherketones,
polymethacrylates, polyacrylates, aromatic polyesters, polyimides,
cellulose, copolymers of polymerisable substances thereof.
12. The medical device of claim 1, wherein the tissue repair member
comprises a bioabsorbable polymer selected from the group
consisting of polyhydroxy acids, polylactides, polyglycolides,
polyhydroxybutyrates, polyhy droxyvaleriates, polycaprolactones,
polydiaxanones, synthetic and natural oligo- and polyaminoacids,
polyphosphazenes, polyanhydrides, polyorthoesters, polyoxaester,
polyphosphates, polyphosphonates, polyalcohols, polysaccharides,
polyethers, resorbable glasses, copolymers of polymerizable
substances thereof.
13. The medical device of claim 1 wherein the first and second
films comprise a biocompatible nonabsorbable polymer selected from
the group consisting of polyolefins, polyester, Nylon, Teflon,
polyvinidenefluoride, and cellulose.
14. The medical device of claim 1 wherein the first and second
films comprise a biocompatible bioabsorbable polymer selected from
the group consisting of polyhydroxy acids, polylactides,
polyglycolides, polyhydroxy butyrates, polyhydroxy valeriates,
polycaprolactones, polydioxanones, synthetic and natural oligo- and
polyamino acids, polyphosphazenes, polyanhydrides, polyorthoesters,
polyphosphates, polyphosphonates, polyalcohols, polysaccharides,
polyethers, polyamides, aliphatic polyesters, aromatic polyesters,
copolymers of polymerizable substances thereof, and resorbable
glasses.
15. The medical device of claim 1, wherein the film pores of the
first and second polymer films have a size ranging from about 0.1
mm to about 5 mm.
16. The medical device of claim 1, wherein the films have a
thickness of about 5 .mu.m to about 50 .mu.m.
17. The medical device of claim 1, wherein the tissue repair member
comprises monofilament fibers.
18. The medical device of claim 1, wherein the tissue repair member
comprises multifilament fibers.
19. The medical device of claim 1, additionally comprising a
polymeric coating.
20. The medical device of claim 1, wherein the pores have a
substantially circular cross-section.
21. The medical device of claim 1, wherein the film pores of the
first and second polymer films comprise slits.
22. A method of repairing a tissue defect, comprising the steps of:
inserting a tissue repair implant device adjacent to a tissue
defect, wherein the device comprises: a tissue repair member having
a plurality of member pores, the repair member having opposed first
and second sides; a first polymer film, having first film pores,
the first polymer film mounted to the first side of the member;
and, a second polymer film, having second film pores, the second
polymer film mounted to the second side of the repair member,
wherein the first film pores are not in alignment with the second
film pores; and, securing the repair device to the tissue
defect.
23. The method of claim 22, additionally comprising the step of
immersing the device in a solution containing an active agent prior
to inserting the tissue repair device.
24. The combination, comprising: a) A tissue implant medical
device, comprising: a tissue repair member having a plurality of
member pores, the repair member having opposed first and second
sides; a first polymer film, having first film pores, the first
polymer film mounted to the first side of the member; and, a second
polymer film, having second film pores, the second polymer film
mounted to the second side of the repair member, wherein the first
film pores are not in alignment with the second film pores; and, b)
An active agent.
25. The combination of claim 24, wherein the active agent is in a
solution.
Description
FIELD OF THE INVENTION
The present invention is directed to soft tissue repair devices
capable of minimizing tissue adhesion between adjacent or opposing
tissue surfaces, more particularly such soft tissue repair devices
capable of rapidly absorbing active agents in an operating room
environment prior to implantation.
BACKGROUND OF THE INVENTION
Tissue repair or reinforcing implants, such as meshes, may be
designed to enable tissue in-growth on one side (e.g., by having
open pores or interstices) and resist tissue in-growth on the
opposing side (e.g., by having a smooth surface such as a film or
non-porous layer, conventionally referred to in this art as an
adhesion barrier). This is important when the mesh implants are
used or implanted in the abdominal area, for example in hernia
repair procedures, where adhesion of the peritoneum (i.e., tissue
ingrowth) to the implant is desired while tissue in-growth or
adhesions on the visceral side is unwanted (i.e., anti-adhesion).
Several conventional products are known in this art and
commercially available having one basically smooth side which is an
adhesion barrier and one porous or rough side for tissue in-growth.
The products may be completely absorbable, completely
non-absorbable, or partially absorbable and partially
non-absorbable. The products may be composites of multiple mesh
layers and adhesion resistant barriers. Certain implants are ready
for use out of the package (e.g., Proceed.RTM. Hernia Mesh, Gore
DualMesh.RTM., and Bard Composix.RTM. Mesh) and other mesh implants
are required to be pre-soaked for several minutes in water or
saline solution prior to implantation in order to swell the
adhesion barrier and make the implant sufficiently soft for
implantation and placement in the patient (e.g., Sepramesh.RTM.;
Parietex.RTM. Composite).
In certain surgical applications, it is desirable for these
implants to deliver a dose of therapeutic or active agent to the
tissues surrounding or adjacent to the implant. To achieve this,
the implant may be preloaded by coating or otherwise impregnating
with the desired active agent by the manufacturer prior to
packaging. However, preloading an implant with an active agent can
be difficult. In addition, the amount of active agent that can be
added to the implant is limited unless the active agent is
delivered in a controlled release manner by the implant for
controlled release to the adjacent tissues. To enable the release
of stored active agent on both sides of an implant, the implant's
active agent reservoir must have fluid communication with each side
of the implant. In the case of an implant consisting of a mesh
contained between opposed outer film layers, this can be made
possible by including pores within the films on both sides of the
mesh. However, providing such pores may allow tissue-to-tissue
contact through the pores located in the films in those areas where
the films are laminated to each other and the pores are in
alignment. Tissue-to-tissue contact will encourage or permit
unwanted tissue adhesions. If pores are present in only one film
layer of the implant, the therapeutic fluid may not be effectively
exposed to the side without any pores. It is also believed that
having pores on only one side will limit tissue fluid flow between
the two sides of the implant. This may result in seroma
formation.
A conventional way to deliver active agents in conjunction with
implanted medical devices is for the surgeon or assistant to dip or
soak the medical device in a solution of the active agent prior to
implantation. As an example, dipping surgical hernia mesh film
constructs in active agent solutions is important to provide an
active-loaded mesh that may also be placed in contact with the
viscera to prevent adhesions. In other applications there may be a
need to place the fabric in contact with the vaginal wall (e.g., a
pelvic mesh) or in contact with the urethra such as with the
GYNECARE.RTM. TVT system from Ethicon, Inc., wherein a perforated
film assembly could be beneficial to prevent erosion of structures
like the bladder, vaginal wall, etc. by a part of the implant.
Currently marketed and commercially available products that are
coated with collagen films (e.g., Parietex.RTM.Composite (PCO)
MESH) have to be incubated for 5-10 minutes in a solution of active
agent, which is relatively time consuming task to perform when in
an operating room (OR) setting and while the patient is under
anesthesia during a procedure. A further drawback with current
commercially available products is that the active agent coatings
are very sensitive to mechanical forces during handling in the
operating room, and using forceps to manipulate or place the
implants can easily destroy such coatings and may lead to
disintegration of the product. Certain commercially available mesh
composite implants such as Composix.RTM. mesh, have a polypropylene
mesh with an ePTFE layer on one side of the mesh. Since both
polypropylene and ePTFE both do not accept hydrophilic liquids very
well, it is anticipated that the delivery of such meshes along with
a coating solution of active ingredient through a trocar to the
surgical site would be difficult.
WO2003041613 A1 describes meshes having two synthetic polymer films
on each side, wherein the films are glued or welded in the pores of
the mesh together; neither perforated pore-containing films on both
sides nor offset pore-containing films are described.
EP1237588 B1 describes a non-absorbable mesh implant covered on one
side with an absorbable film made from natural (hyaluronic acid) or
natural-derived (CMC) materials which may have pores, and in
between an adhesive such as a polylactide co-polymer. A drug may be
incorporated in any portion of the prosthesis to provide for
controlled release of the drug into the body.
WO2003099160 A1 describes knobbed films that may be present on both
sides of a fabric implant, wherein both films can have holes that
are arranged in a pattern. Filling the knobs with an active agent
is taught, however dipping or filling the area outside the knobs is
not indicated.
EP 1541183 A1 describes a mesh having absorbable polymer films with
two different absorption times. US20030017775 A1 describes a
composite intraluminal prosthesis which is preferably used as a
vascular prosthesis and includes a layer of ePTFE and a layer of
textile material, which are secured together by an elastomeric
bonding agent. The ePTFE layer includes a porous microstructure
defined by nodes interconnected by fibrils. The adhesive bonding
agent is preferably applied in solution so that the bonding agent
enters the pores of the microstructure of the ePTFE.
There is a need in this art for tissue implant devices that offer
advantages over the tissue devices of the prior art, including
providing a device that permits rapid absorption of active agents
while providing tissue separating properties at least for a certain
period of time. In particular, tissue implants are needed that are
well suited to fast dip coating processes for providing active
implants with effective amounts of active agents in a quick and
efficient manner, particularly for dipping in the operating room.
Also needed are fast, dippable mesh-laminate implants suitable for
an inline process (pulling through a coating bath), wherein the
impregnation time of the active agent into the mesh implant is
reduced.
SUMMARY OF THE INVENTION
Accordingly, novel tissue repair implant medical devices are
disclosed. The tissue implant medical device of the present
invention has a tissue repair member having a plurality of member
openings or pores and is preferably a fabric such as a mesh. The
repair member has opposed first and second sides. A first polymer
film, having first film pores, is mounted on the first side of the
member. A second polymer film, having second film pores, is mounted
on the second side of the member. The first film pores are not in
alignment with the second film pores, that is, the pores are
offset, such that tissue-to-tissue contact is substantially
prevented.
Yet another aspect of the present invention is a method of
repairing a tissue defect, utilizing the above-described tissue
repair implant devices.
Still yet another aspect of the present invention is a combination
of the above-described tissue repair implant device and an active
agent.
The tissue repair devices of the present invention have many
advantages. One advantage of the devices of the present invention
is to allow an active agent-containing liquid to impregnate the
repair fabric and the films in a short period of time, while not
exposing facing or adjacent tissue to direct contact once
implanted, thereby minimizing the possibility of tissue adhesions.
The devices of this invention are particularly well suited to
dipping into solutions of active agents, whether in a batch process
(such as in an operating room environment) or through a
manufacturing process, and demonstrate fast absorption of
liquids.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a perspective view of an embodiment of a tissue repair
device of the present invention.
FIG. 2 illustrates a magnified partial cross-section of the tissue
repair device of FIG. 1 along Viewline 2-2.
FIG. 3 is a picture of a section of one embodiment of a tissue
repair device of the present invention made in accordance with
Example 1 showing the relationship of the top film pores in the top
porous film to the bottom film pores in the bottom porous film, and
central mesh.
FIG. 4 is an enlarged picture of a pore in a film according to one
embodiment of the present invention made in accordance with Example
1.
DETAILED DESCRIPTION OF THE INVENTION
The implantable tissue repair medical devices of the present
invention as described herein consist of a composite of a tissue
repair fabric member and porous adhesion barrier films mounted on
opposed outer sides of the tissue repair fabric. Both of the films
have pores, such that the tissue repair devices can be easily and
quickly dipped, independent of the size of the device and the
manner in which it is placed, in a dipping bath, i.e., horizontally
or vertically. Due to the non-overlapping or nonaligned orientation
of the pores in the opposing films of the devices of the present
invention (i.e., offset pores), the devices may be placed in
contact with viscera with little concern since the aforementioned
pore orientation substantially or completely prevents
tissue-to-tissue contact and allows at the same time tissue-to-mesh
contact on both sides (good ingrowth). Also, less seroma formation
is expected (and hence less infection), due to improved fluid flow
through the implant.
Surgical repair fabrics suitable for use as the intermediate or
middle layer of the tissue repair devices of the present invention
include conventional meshes, woven fabrics, and tapes for surgical
applications. Other fabrics or materials include perforated
condensed ePTFE films and nonwoven fabrics having pore sizes of at
least one millimeter.
The fabrics will have open pores with a size of at least 1 mm. By
"open pores" is meant openings that extend from one side of the
fabric to the opposed side, providing a pathway through the
fabric.
Depending upon the intended use of the tissue repair device, a
biocompatible long-term-stable polymer may be used to manufacture
the fabric repair member. By a long-term-stable polymer is meant a
non-resorbable biocompatible polymer, or a bioabsorbable polymer
which absorbs or degrades slowly, for example which possesses at
least 50% of its original tearing strength in vivo 60 days after
implantation. The latter group includes substances such as
polyamides, which generally are regarded as resistant, as they are
not designed as resorbable materials, but are attacked over time by
body tissue and tissue fluids. Preferred materials for the fabric
repair member include polyhydroxy acids, polylactides,
polyglycolides, polyhydroxy butyrates, polyhydroxy valeriates,
polycaprolactones, polydioxanones, synthetic and natural oligo- and
polyamino acids, polyphosphazenes, polyanhydrides, polyorthoesters,
polyphosphates, polyphosphonates, polyalcohols, polysaccharides,
polyethers, polyamides, aliphatic polyesters, aromatic polyesters,
copolymers of polymerizable substances thereof, resorbable
glasses.
Particularly preferred materials for the fabric repair member
include polypropylene and mixtures of polyvinylidene fluoride and
copolymers of vinylidene fluoride and hexafluoropropene, PTFE,
ePTFE, and cPTFE, but other conventional biocompatible materials
are also useful. The fabric repair members may be constructed from
monofilaments, multifilaments, or combinations thereof.
The fabric repair member may contain, in addition to a long-term
stable polymer, a resorbable polymer (i.e., bioabsorbable or
biodegradeable). The resorbable and the long-term stable polymer
preferably contain monofilaments and/or multifilaments. The terms
resorbable polymers and bioabsorbable polymers are used
interchangeably herein. The term bioabsorbable is defined to have
its conventional meaning. Although not preferred, the fabric repair
member may be manufactured from a bioabsorbable or bioabsorbable
polymers without any long-term stable polymers.
The films that are used to manufacture the tissue repair implant
devices of the present invention will have a thickness that is
sufficient to effectively prevent adhesions from forming The
thickness will typically range from about 1 .mu.m to about 500
.mu.m, and preferably from about 5 .mu.m to about 50 .mu.m. The
films suitable for use as the first and second films of the tissue
repair devices of the present invention include both bioabsorbable
and non-absorbable films. The films are preferably polymer-based
and may be made from various conventional biocompatible polymers.
Non-resorbable or very slowly resorbable substances include
polyalkenes (e.g. polypropylene or polyethylene), fluorinated
polyolefins (e.g. polytetrafluoroethylene or polyvinylidene
fluoride), polyamides, polyurethanes, polyisoprenes, polystyrenes,
polysilicones, polycarbonates, polyarylether ketones (PEEKs),
polymethacrylic acid esters, polyacrylic acid esters, aromatic
polyesters, polyimides as well as mixtures and/or co-polymers of
these substances. Also useful are synthetic bioabsorbable polymer
materials for example, polyhydroxy acids (e.g. polylactides,
polyglycolides, polyhydroxybutyrates, polyhydroxyvaleriates),
polycaprolactones, polydioxanones, synthetic and natural oligo- and
polyamino acids, polyphosphazenes, polyanhydrides, polyorthoesters,
polyphosphates, polyphosphonates, polyalcohols, polysaccharides,
polyethers. However, naturally occurring materials such as
collagen, gelantin or natural-derived materials such as
bioabsorbable Omega 3 fatty acid crosslinked gel films or
oxygenized regenerated cellulose (ORC) can also be used.
The films used in the tissue repair devices of the present
invention may cover the entire outer surfaces of the repair fabric
member or a part thereof. In some cases, it is beneficial to have
films overlapping the borders of the repair fabric. The term border
used herein means a peripheral edge or central edge if there is a
hole in the mesh, e.g., for receiving an anatomical structure like
the bowel for treating or preventing parastomal hernia or the
spermic cord.
The porous films used to construct the devices of the present
invention will have open pores. Perforated or porous films may be
prepared using conventional processes such as mechanical cutting or
punching, by applying energy such as laser light, ultrasound,
microwave, heat or corona/plasma. Chemical etching or injection
molding molding processes can also be used. Conventional foaming
processes including lyophilization may also be used to create the
open porous structure.
The pores in the films may be made in the form of multiple slits or
incisions without cutting out or removing material from the film,
or may have a certain length and width or diameter resulting from
the removal of material from the film, or may be openings resulting
from the absence of polymeric material at locations within the
film. The pores may have various geometric configurations including
circular, oval, rectangular, diamond-shaped, square, triangular,
polygonal, irregular, combinations thereof and the like. It is
particularly preferred that the pores are bore holes extending
through the film having a circular cross-section.
The films may be perforated before or after assembling the device,
or the films may be manufactured in such a manner that they contain
pores. However, it will be appreciated by those skilled in the art
that precautions have to taken to prevent damage the fabric member
or the second film when perforating an assembled device.
For ease of manufacturing during assembling and a desired
wetability with aqueous coatings (i.e., liquid has to go in/air has
to go out), the perforation/pore size should typically be at least
0.2 mm to 5 cm, preferably 0.5 to 7 mm, most preferably 1 to 5 mm
at least in one direction. As previously mentioned, the pores can
have different sizes and shapes. Additionally, depending on the
manufacturing technique, the edges of the film pores may be smooth
or rough. Also, the edges of the pores may be embossed and rounded
or beveled.
The films can be joined together in various conventional manners,
for example by sewing, gluing, welding, and laminating. The
joining/connection can be about the periphery, in the center
region, or over the whole assembly as a point linear or overall
connection, making sure that the pores of the top and bottom films
are substantially offset.
The films can be connected to each other and/or to the repair
fabric member in variety of different conventional ways, e.g.,
sewn, embroidered, bonded (including by thermal means) in partial
regions (e.g., in points or along lines or strips, such as the
peripheral edge), or welded thermally including ultrasonically. The
welding techniques also include, in the wider sense, thermal
deformation of at least one of the films (below the melting point
of one film). The implant can optionally have embroidered
structures designed as reinforcements, e.g. rib-like
structures.
Particularly preferred for the devices of the present invention is
a film-to-film connection using heat lamination techniques,
optionally by using an additional biocompatible melt glue such as
polydioxanone as a relatively low melting bioabsorbable polymer.
Other soluble polymers such as polylactide, polycaprolactone or
copolymers thereof might be used as solvent glues. Reactive glues
like cyanoacrylates or isocyanantes or oxiranes may also be used if
biocompatible.
Referring now to FIGS. 1 and 2, a tissue repair implant device 1 of
the present invention is seen. The device 1 is seen to have a
central or middle fabric member 20. Member 20 is seen to be a
substantially flat mesh knitted from fibers 22. The member 20 is
seen to have a plurality of mesh openings or mesh pores 25 formed
between the fibers 22. The member 20 has opposed outer sides 28.
The device 1 is also seen to have first and second porous adhesion
barrier films 10 and 30 mounted, respectively, to the fabric member
20 on opposed sides 28. In this embodiment of the tissue repair
device of the present invention, the films 10 and 30 are connected
together through the mesh openings or mesh pores 25. The first film
10 is seen to have film pores 12 extending therethrough, while the
second film 30 has film pores 32 extending therethrough. The pores
12 and the pores 32 are arranged to be offset so as to not be in
alignment, thereby not providing a direct pathway between opposed
pores 12 and 32.
The term active agents includes but is not limited to therapeutic
agents. The selection of active agents that can be used in
combination with medical devices of the present invention depends
upon the desired patient benefit intended to be derived. For
example, it may be advantageous to provide an implant of the
present invention that has at least one biologically active or
thereapeutic ingredient which can optionally be released locally
after the implantation. Substances which are suitable as active or
therapeutic agents may be naturally occurring or synthetic, and
include and are not limited to, for example, antibiotics,
antimicrobials, antibacterials, antiseptics, chemotherapeutics,
cytostatics, metastasis inhibitors, antidiabetics, antimycotics,
gynecological agents, urological agents, anti-allergic agents,
sexual hormones, sexual hormone inhibitors, haemostyptics,
hormones, peptide-hormones, antidepressants, vitamins such as
Vitamin C, antihistamines, naked DNA, plasmid DNA, cationic DNA
complexes, RNA, cell constituents, vaccines, cells occurring
naturally in the body or genetically modified cells. The active or
therapeutic agent may be present in various forms including in an
encapsulated form or in an adsorbed form. With such active agents,
the patient outcome may be improved or a therapeutic effect may be
provided (e.g., better wound healing, or inflammation inhibition or
reduction).
One preferred class of active agents is antibiotics that include
such agents as gentamicin or ZEVTERA.TM. (ceftobiprole medocaril)
brand antibiotic (available from Basilea Pharmaceutica Ltd., Basel
Switzerland). Other active agents that may be used are highly
effective, broad band antimicrobials against different bacteria and
yeast (even in the presence of bodily liquids) such as octenidine,
octenidine dihydrochloride (available as active ingredient in
Octenisept.RTM. disinfectant from Schulke & Mayr, Norderstedt,
Germany as), polyhexamethylene biguanide (PHMB) (available as
active ingredient in Lavasept.RTM. from Braun, Switzerland),
triclosan, copper (Cu), silver (Ag), nanosilver, gold (Au),
selenium (Se), gallium (Ga), taurolidine, N-chlorotaurine, alcohol
based antiseptics such as Listerine.RTM. mouthwash, N
.alpha.-lauryl-L-arginine ethyl ester (LAE), myristamidopropyl
dimethylamine (MAPD, available as an active ingredient in
SCHERCODINE.TM. M), oleamidopropyl dimethylamine (OAPD, available
as an active ingredient in SCHERCODINE.TM. O), and stearamidopropyl
dimethylamine (SAPD, available as an active ingredient in
SCHERCODINE.TM. S), fatty acid monoesters, and most preferably
octenidine dihydrochloride (hereinafter referred to as octenidine),
Taureolidine, and PHMB.
One preferred class of active agents are local anesthetics that
includes such agents as: Ambucaine, Benzocaine, Butacaine,
Procaine/Benzocaine, Chloroprocaine, Cocaine, Cyclomethycaine,
Dimethocaine/Larocaine, Etidocaine, Hydroxyprocaine, Hexylcaine,
Isobucaine, Paraethoxycaine, Piperocaine, Procainamide,
Propoxycaine, Procaine/Novocaine, Proparacaine,
Tetracaine/Amethocaine, Lidocaine, Articaine, Bupivacaine,
Dibucaine, Cinchocaine/Dibucaine, Etidocaine, Levobupivacaine,
Lidocaine/Lignocaine, Mepivacaine, Metabutoxycaine, Piridocaine,
Prilocalne, Propoxycaine, Pyrrocaine, Ropivacaine, Tetracaine,
Trimecaine, Tolycaine, combinations thereof, e.g.,
Lidocaine/prilocalne (EMLA) or naturally derived local anesthetics
including Saxitoxin, Tetrodotoxin, Menthol, Eugenol and pro-drugs
or derivatives thereof.
In some instances, the active or therapeutic agent is provided in a
solution. The solution may comprise any suitable solvent compatible
with the selected active ingredient. The solution may be
water-based and may contain at least one of the following
additional conventional ingredients: a surface active agent, a
polymer, protein or dye. Polymers are used to adjust the release
rate. Depending on the active agent and release required, polymer
solvent mixtures for coatings might be advantageous.
Additionally, a contrast agent may be incorporated into the devices
of the present invention. Such a contrast agent may be a
biocompatible dye to create a visual marker as described in
EP1392198B1 which is incorporated by reference or an agent such as
a gas or gas creating substance for ultrasound contrast or MRI
contrast, such as metal complexes like GdDTPA or superparamagnetic
nanoparticles (Resovist.TM. or Endorem.TM.) as taught in the EP
1324783 B1, which is incorporated by reference. X-Ray visible
substances might be included as shown in the EP1251794B1
(incorporated by reference) including pure zirconium dioxide,
stabilized zirconium dioxide, zirconium nitride, zirconium carbide,
tantalum, tantalum pentoxide, barium ulphate, silver, silver
iodide, gold, platinum, palladium, iridium, copper, ferric oxides,
not very magnetic implant steels, non-magnetic implant steels,
titanium, alkali iodides, iodated aromatics, iodated aliphatics,
iodated oligomers, iodated polymers, alloys of substances thereof
capable of being alloyed. The contrast agents may be included in or
on the mesh, or in or on the films.
Additionally, swelling or gel forming substances might be added to
the mesh and/or films. This has the advantage of improving the
uptake of the dipping solution. The substances include proteins
such as collagen or gelatin, surfactants such as PPO-PEO block
copolymers (Pluronics), polysorbates such as polysorbate 20, 40,
60, 65, 80 (Tweens), or spans like Span 20 (Sorbitan monolaurate),
Span 40 (Sorbitan monopalmitate), Span 60 (Sorbitan monostearate),
Span 65 (Sorbitan tristearate), Span 80 (Sorbitan monooleate),
phospholipids, hydophilic natural or synthetic polymers such as
alginate, dextrane, chitosane, carracen, PEG, PVA, PVP, CMC,
HES.
Hydrogel forming polymers may be obtained upon the polymerization
or polyaddition or polycondensation containing at least one of the
substances selected from the following group: polymerized
hydroxyethyl methacrylate (HEMA); polymerized hydroxypropyl
methacrylate (HPMA); polymerized a-methacryloyl-o-methoxy
polyethylene glycol; polymerized polyethylene glycol-bisacrylate;
resorbable prepolymers of type A-B-C-B-A with A=acryl or methacryl
groups, B=hydrolytically splittable and containing polymers of
lactide, glycolide, 2-hydroxybutyric acid, 2-hydroxyvaleriac acid,
trimethylene carbonate, polyorthoesters, polyanhydrides,
polyphosphates, polyphosphazenes and/or polyamides and/or
copolymers thereof, and C=hydrophilic polymers, in particular
polyethylene glycol (PEG), polyvinyl alcohol (PVA), polyvinyl
pyrrolidone (PVP), poly N-isoprolyacrylamide (PNiPAAM).
The following examples are illustrative of the principles and
practice of the present invention although not limited thereto.
Example 1
Lightweight Mesh Laminated Between Two Porous Monocryl.RTM.
Films
A lightweight polypropylene mesh having the same knitting structure
as Ultrapro.RTM. brand mesh available from Ethicon, Inc.,
Somerville, N.J. U.S.A. but without the absorbable Monocryl.RTM.
filaments-(poliglecaprone 25) was prepared. This mesh was heat
laminated between two film layers. The first film consisted of 20
.mu.m thick poliglecaprone 25 Monocryl.RTM. film that was extruded
and laminated with an 8 .mu.m thick poly-p-dioxanone (PDS) film.
The pre-laminate was laser-cut with 1 mm holes or pores with a
hole-to-hole distance of 5 mm. A second laminate layer comprising
poliglecaprone 25 Monocryl film having a thickness of
.sub.------------ was laser cut and pre-cut in the same manner as
the first laminate layer above. Both films were placed in such a
way that the holes or pores were not in alignment (i.e., offset)
and were mounted as opposed outer films on the outer surfaces of
the polypropylene mesh. The film mesh construct was laminated in a
heat press between several layers of baking paper and chilled
between 2 metal plates (30 seconds, 120.degree. C. and chilled for
about 30 minutes between metal plates).
An 8.times.11 cm sample of this laminate was placed horizontally in
a dish containing 0.1% (wt/wt) of antibacterial crystal violet
aqueous solution as a model antibacterial solution.
The laminated mesh, including the mesh and the films, was
completely impregnated with the solution within 10 seconds.
A film laminate having films with no holes or pores of the same
size was similarly tested and 1 required a significantly longer
time to impregnate. The impregnation time for the film laminates
without pores or holes was observed to be about 5-10 minutes or
longer.
After drying the coated impregnated mesh laminate it was observed
that the film gluing area in the center of the mesh pores is
basically free of the antibacterial dye and the mesh and the mesh
surrounding area between the films is stained (about 30%-50% of the
total area).
A picture of a section of one embodiment of a tissue repair device
of the present invention made in accordance with this Example 1 is
seen in FIG. 3. It shows the relationship of the top film pores in
the top porous film to the bottom film pores in the bottom porous
film, and a central mesh. FIG. 4 is an enlarged picture of a pore
in a film according to one embodiment of the present invention made
in accordance with this Example 1.
Example 2
Horizontal Dipping
This example demonstrated the wetting capabilities of the tissue
repair devices of the present invention compared with non-porous
devices.
Several 8.times.12 cm laminates with pore-containing films (pore
diameter=1 mm, pore spacing=5 mm) were prepared according to
Example 1. Several 8.times.12 cm laminates with nonporous films
were prepared according to Example 1 with the exception that
nonporous films were used in place of the porous films. The dry
weight was determined for the porous and nonporous laminates.
The laminates were placed horizontally into a flat vessel
containing 500 ml 0.2% Lavasept solution for 10 seconds (made from
a Lavasept concentrate (20% PHMB), Lot 7383M03). The laminates were
taken out and slightly shaken, to remove excess of liquid and
weight was determined again.
Table 1 contains the results of the horizontal dipping
experiments.
TABLE-US-00001 TABLE 1 HORIZONTAL DIPPING EXPERIMENTS Dry Wetted
Weight Weights (Before (After 10 s Weight Avg dipping) dipping)
increase increase Laminate [grams] [grams] (%) % SD % 1) Porous
0.7801 2.0006 256 -- -- 2) Porous 0.7707 1.9505 253 -- -- 3) Porous
0.8013 2.0184 252 254 2 4) Nonporous 0.9558 1.4962 157 -- -- 5)
Nonporous 0.9512 1.4957 157 -- -- 6) Nonporous 0.9604 1.8926 197
170 23
All of the pore-containing laminates appeared to be completely
wetted including in between the films. The nonporous laminates were
starting to wet between films in the periphery (in particular
Laminate 6 was about a quarter wetted between the films after 10
seconds).
The pore-containing laminates had about 70% higher liquid uptake
after 10 seconds (170%.fwdarw.254%).
The weight gain of the nonporous laminates seem to be entirely due
to liquid on top of the films, while the increase in the
pore-containing laminates was additionally due to liquid uptake
between the films.
Example 3
Horizontal Dipping in the OR and Handling Properties
Laminates were prepared in accordance with Example 1, but in an 18
cm.times.14 cm size. Pore-containing and nonporous laminates were
placed through a conventional 12 mm trocar inserted through to the
abdominal cavity of a swine. The implants were easily movable
(sliding) at the intestine and then placed against the abdominal
wall. Pore-containing and nonporous laminates were removably
self-attaching to the abdominal wall. No instrument was needed to
keep them up in place.
The same handling behavior was observed even for 10 second isotonic
saline pre-wetted implants.
With the area weights calculated from Table 1 test articles had an
attachment force to the abdominal wall greater than their own area
weight of 20 mg/cm.sup.2 in the case of the dipped perforated film
(calculated from 2 g of the 8.times.11 cm perforated wet implant in
tab 1).
The devices of this invention were seen to be useful for adhesion
prevention as a film barrier and potential drug delivery carrier in
surgical fields such as pelvic, colorectal and plastic surgery.
Example 4
Porous cPTFE Sheet Between 2 Perforated Films
A 10.times.10 cm Omyra mesh (B. Braun) was laminated according to
Example 1 between perforated Monocryl.RTM. films at 120.degree. C.
for 5 minutes and then chilled down between two cold metal plates
for additional 30 minutes. The films were stable laminated within
the pores of the mesh, usual handling and bending of the composite
implant indicated no delamination. Optical control showed no
overlap of the film pores, that is, offset pores.
Example 5
Perforate Film Laminate with Octenidine+Coating Polymer Dip
Coating
A 16 cm.times.16 cm mesh laminate was prepared according to Example
1.
1 kg of a coating solution was prepared containing 1.5 g Octenidine
Dihydrochloride+9 g Coating Polymer PEDG/PLLA 60/40 in accordance
with Example 5b of commonly-assigned, co-pending patent application
Ser. No. 12/609,101 filed on Oct. 30, 3009 (incorporated by
reference)+889 g Aceton+100 g deionized water.
The coating solution was purged in a thin and high vertical
rectangular coating bath (length .about.20 cm, high .about.20 cm,
with .about.2 cm) and the implant sheet dwell time in the bast was
about 5 minutes and it was then pulled out with a speed of 3
mm/sec, allowed to dry (about 30 minutes at room temperature/normal
pressure and then over night in a vacuum chamber evaporated by an
oil pump.), punched into 1.5 cm circles, packaged, and sterilized
using a conventional ethylene oxide sterilization process.
After sterilization the disks had a content of 2200 ppm of
Octenidine with a standard deviation of 11% between 3 mesh
disks.
In an FCS containing S. aureus assay the mesh disks showed strong
antibacterial activity when incubated for 4 hours in 3 ml
bacteria/serum mixture of at least 1 g5 compared to the uncoated
control.
Example 6
Surgical Procedure Using the Tissue Repair Implant Devices of the
Present Invention
A patient with a ventral hernia is prepared for surgery in a
conventional manner, and anesthetized in a conventional manner. The
ventral hernia repair procedure is performed in the following
manner using a tissue repair implant device of the present
invention.
LVHR (Laparoscopic Ventral Hernia Repair)
After placing the trocars, setting the pneumoperitoneum, clearing
the hernia sack of its contents and lyses of adhesions, the surgeon
identifies the size of the hernia defect.
An appropriate-sized mesh (according to the present invention)
having a certain overlap to cover the hernia defect is tightly
rolled up and passed into the abdomen through a 10 mm or 12 mm
port. If needed the mesh is dipped for a few seconds into a vessel
containing an active solution such as antibiotics or antiseptics
prior to passage through a trocar into the patient.
After the trocar passage the mesh unrolls by itself or unrolls with
minimal assistance from an appropriate surgical instrument on the
intestine and is moved and positioned to the right place and
orientation. Then the mesh is lifted up at the abdominal wall to
cover the defect and self attaches or is attached to the abdominal
wall. Fixation is performed in a conventional manner using
transabdominal sutures or staples.
Although this invention has been shown and described with respect
to detailed embodiments thereof, it will be understood by those
skilled in the art that various changes in form and detail thereof
may be made without departing from the spirit and scope of the
claimed invention.
* * * * *